Sialylation in the Maintenance and Metabolic Plasticity of Neural Stem Cell-Like Brain Tumor Cells

唾液酸化在神经干细胞样脑肿瘤细胞的维持和代谢可塑性中的作用

基本信息

批准号：
10538769
负责人：
Anita Borton Hjelmeland
金额：
$ 50.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538769
关键词：
ALCAM gene Adult Affinity Area Astrocytes Behavior Biological Assay Biology Brain Neoplasms Brain Pathology Cancer Biology Cell Communication Cell Differentiation process Cell Maintenance Cell Surface Proteins Cell Survival Cell membrane Cell surface Cells Cellular Metabolic Process Cessation of life Charge Chemoresistance Data Development Differentiation Antigens Enzymes GLUT-3 protein Genetic Glioblastoma Glucose Glucose Transporter Glycoproteins Golgi Apparatus Growth Growth Factor Receptors Human Integrins Lead Lectin Link Longitudinal Studies Maintenance Malignant Childhood Neoplasm Measures Mediating Mediator of activation protein Messenger RNA Metabolic Metabolism Modification Molecular Conformation Molecular Mechanisms of Action Mus Nature Neuronal Plasticity Neurons Neurosphere Nutrient Oligosaccharides Pathway interactions Pharmacology Phenotype Phosphorylation Polysaccharides Post-Translational Protein Processing Property Proteins Proteomics Publishing Research Resistance Role SLC2A1 gene Sialic Acids Sialyltransferases Signal Transduction Site Therapeutic Intervention Tumor Biology beta-galactoside cell growth cell motility differential expression effective therapy experimental study extracellular vesicles glucose uptake glycosylation improved inhibitor innovation inorganic phosphate insight knock-down metabolome migration mind control neoplastic cell nerve stem cell neurodevelopment novel nutrient deprivation paralogous gene protein expression protein function protein structure function receptor self-renewal sialylation stem stem cells stem-like cell temozolomide tumor growth tumor metabolism tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT One of the least-investigated areas of research in brain pathologies is glycosylation, which is a critical regulator of cell surface protein structure and function. ST6Gal1 is the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion. Sialylation adds a negatively-charged, sialic acid to the end of an oligosaccharide chain of a glycoprotein. Sialylation of distinct protein subsets has important effects on conformation, clustering and cell surface retention as has been found for some integrins, growth factor receptors and death receptors. Through this mechanism, ST6Gal1 regulates phenotypes including survival, invasion, and stem cell maintenance. However, there are critical gaps in our understanding of how ST6Gal1-mediated sialylation impacts brain tumor cell growth or differentiation state, and there are no studies identifying a2,6 sialylated proteins or ST6Gal1 regulated pathways in brain tumors. Our preliminary data demonstrate a novel, pro-tumorigenic role for a2,6 sialylation and ST6Gal1 in the deadly brain tumor glioblastoma. We seek to determine whether ST6Gal1- mediated a2,6 sialylation promotes brain tumor initiating cell maintenance and metabolic plasticity. In the short- term, our results will lead to an improved understanding of how ST6Gal1-mediated a2,6 sialylation regulates protein expression and function to impact brain tumor propagation. In the long-term, these studies may offer the potential for new mechanisms of therapeutic intervention for the treatment of brain tumors as ST6Gal1 inhibitors are under development.

项目摘要/摘要糖基化是脑病理学研究最少的研究领域之一，这是细胞表面蛋白结构和功能。 ST6GAL1是a2,6乙二酸N-糖基化的主要酶注定要用于质膜或分泌的蛋白质。乙二醇为带负电荷的唾液酸添加到糖蛋白的寡糖链的末端。不同蛋白质亚群的溶解作用对对于某些整合素，生长因子受体的构象，聚类和细胞表面保留率和死亡受体。通过这种机制，ST6GAL1调节表型，包括生存，入侵和干细胞维护。但是，我们对ST6GAL1介导的溶性如何的理解存在关键的差距影响脑肿瘤细胞生长或分化状态，并且没有研究鉴定A2,6溶解蛋白或ST6GAL1调节脑肿瘤的途径。我们的初步数据证明致命的脑肿瘤胶质母细胞瘤中的A2,6溶解和ST6GAL1。我们试图确定ST6GAL1-- 介导的A2,6溶解酶促进了脑肿瘤，从而启动细胞维持和代谢可塑性。在短暂的术语，我们的结果将提高人们对ST6GAL1介导的A2,6乙二醇如何调节蛋白质的理解。影响脑肿瘤传播的表达和功能。从长远来看，这些研究可能会提供潜力对于新的治疗脑肿瘤的治疗干预机制，作为ST6GAL1抑制剂发展。